The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to 8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene derivatives which inhibit ATR (Ataxia telangiectasia mutated and Rad3-related kinase). The compounds of this invention are therefore useful in treating diseases such as cancer.
The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
The tricyclic chemical entities of the present invention are inhibitors of ATR and have a number of therapeutic applications, particularly in the treatment of cancer.
Cancers are the consequence of uncontrolled cell growth of a wide variety of different tissues. In many cases the new cells penetrate into existing tissue, or they metastasize into remote organs. Cancers occur in a wide variety of organs and often progress in a manner specific to the tissue. The term “cancer” as a generic term therefore describes a large group of defined diseases of different organs, tissue and cell types.
In 2008, over 12 million people worldwide were diagnosed with cancer. In the same year, approx. 7.5 million deaths were assumed to be a consequence of these diseases (Globocan 2008 Report). In the USA alone, in 2012, more than 1.6 million new cases and more than 500 000 deaths were predicted from cancers. The majority of these new cases relate to cancers of the colon (˜100 000), lung (˜230 000), breast (˜230 000) and prostate (˜240 000) (American Cancer Society, Cancer Facts and Figures 2012).
Many current cancer treatments, including chemotherapeutic agents and ionizing radiation, induce DNA damage and replication fork stalling, thereby activating cell cycle checkpoint pathways and leading to cell cycle arrest. A variety of studies have shown that this response is an important mechanism that helps cancer cells survive the treatments. These findings have prompted the development of agents targeting DNA damage response signalling pathways.
ATR is a member of phosphatidylinositol kinase-related kinase (PIKK) protein family, and is activated by a wide variety of DNA damage events. In particular, ATR is essential to coordinate the response to replicative stress (RS), which stands for the pathological accumulation of single stranded DNA (ssDNA). The recombinogenic nature of ssDNA leads to chromosomal rearrangements that are a hallmark of cancer. In response to RS, ATR triggers arrest of the cell cycle in the S and G2/M stages by phosphorylation of CHK1.
ATR can prevent cancer development, as the ATR checkpoint response might limit the expansion of precancerous cells undergoing RS as a result of oncogene activation. Moreover, because the ATR-CHK1 checkpoint pathway serves to ensure cell survival after RS, a normal and robust ATR-CHK1 checkpoint may be a mechanism of resistance to chemotherapy and may allow cancer cells to survive with high endogenous levels of RS.
Inhibition of ATR-CHK1 pathway components could potentially enhance the effectiveness of replication inhibitors. In addition, ATR inhibition may be particularly toxic for cells with high levels of RS, such as those expressing oncogenes or lacking tumour suppressors. In these cells, strong limitation of ATR activity (for example, by use of an ATR inhibitor) would generate lethal amounts of RS leading to cell death.
A potential advantage of sensitizing cells in this way would be the capacity to lower the doses of the replication inhibitors. This would result in reduced toxicity to haematological and gastrointestinal organ systems among others, if the normal cells are not sensitized to the same extent. Specificity of the replication inhibitor for causing cancer cell death may be assisted by the fact that untransformed cells have more robust S and G2 checkpoints than tumour cells. For example, many cancers have mutations in p53 or other components of the p53 pathway, leading to reliance on the S and G2 checkpoints to arrest the cell cycle and provide for repair and survival. Inhibition of the S and G2 checkpoints may then preferentially kill these p53 deficient tumour cells.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
There is a lack of potent inhibitors of ATR. Therefore, a need exists for chemical entities that selectively inhibit ATR for clinical use or for further study of the ATR response.
It has been found that an (R) methyl group on the tricyclic pyrimidine core improves significantly the ATR inhibition potency. Furthermore, 5′ substituted azaindoles can improve ATR potency and decrease hERG activity.
An (R) methyl group on the 8,12-dioxa-1,3,5-triazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene core significantly improves cellular ATR potencies.
It has been found that the compounds according to the invention and salts thereof have very valuable pharmacological properties while being well tolerated.
The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.
The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in vitro tests. Typically, a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow active agents such as anti IgM to induce a cellular response such as expression of a surface marker, usually between about one hour and one week. In vitro testing can be carried out using cultivated cells from blood or from a biopsy sample. The amount of surface marker expressed is assessed by flow cytometry using specific antibodies recognising the marker.
The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.